Secondary cancer risk assessment in healthy organs following craniospinal irradiation.

INTRODUCTION: Medulloblastoma is a central nerves tumor that often occurs in pediatrics. The main radiotherapy technique for this tumor type is craniospinal irradiation (CSI), through which the whole brain and spinal cord are exposed to radiation. Due to the immaturity of healthy organs in pediatrics, radiogenic side effects such as second cancer are more severe. Accordingly, the current study aimed to evaluate the risk of secondary cancer development in healthy organs following CSI. MATERIALS AND METHODS: Seven organs at risk (OARs) including skin, eye lens, thyroid, lung, liver, stomach, bladder, colon, and gonads were considered and the dose received by each OAR during CSI was measured inside an anthropomorphic RANDO phantom by TLDs. Then, the mean obtained dose for each organ was used to estimate the probability of secondary malignancy development according to the recommended cancer risk coefficients for specific organs. RESULTS: The results demonstrated that the stomach and colon are at high risk of secondary malignancy occurrence, while the skin has the lowest probability of secondary cancer development. The total received dose after the treatment course by all considered organs was lower than the corresponding tolerable dose levels. CONCLUSIONS: From the results, it can be concluded that some OARs during CSI are highly at risk of secondary cancer development. This issue may be of concern due to organ immaturity in pediatrics which can intensify the radiogenic effects of radiation exposure. Accordingly, strict shielding the OARs during craniospinal radiotherapy and/or sparing them from the radiation field through modern techniques such as hadron therapy is highly recommended.

Comparing two radiotherapy techniques of whole central nervous system tumors, considering tumor and critical organs' dose provided by treatment planning system and direct measurement.

AIMS: In central nervous system (CNS) tumors, surgery combined with radiotherapy may cure many tumors. The basic technique in conventional radiotherapy is craniospinal radiotherapy; in this technique, spinal cord can be treated with electron or photon beams. This study was aimed to compare two radiotherapy techniques in craniospinal radiotherapy, (a) treatment of spine with a single photon beam and (b) with a combination of photon and electron beams. MATERIALS AND METHODS: The two techniques were planned. In the first technique, both brain and spine were irradiated with 6 MV photon beams. In the second technique, brain was irradiated with 6 MV photon and spine with 18 MeV electron beams. To compensate the dose deficiency in lumbar area, an anterior field of 15 MV photon beam was also applied in the second technique. The dose to target volume and organ at risks (OARs) were measured by thermoluminescent dosimeter and compared with the corresponding values calculated by Isogray treatment planning system. RESULTS: OARs including heart, mandible, thyroid, and lungs received lower dose from technique 2 compared with technique 1; kidneys were exceptions which received higher dose in the technique 2. CONCLUSIONS: The dose to thyroid, mandible, heart, and lungs were lower in technique 2, while kidneys received higher dose in technique 2. This was caused by using the anterior 15 MV photon beam. Based on these results, for children, instead of photon beam for treatment of spinal cord, it is wiser to use electron beam.

Promising survival rate but high incidence of treatment-related mortality after reduced-dose craniospinal radiotherapy and tandem high-dose chemotherapy in patients with high-risk medulloblastoma.

BACKGROUND: In this study, we report the follow-up results of reduced dose of craniospinal radiotherapy (CSRT) followed by tandem high-dose chemotherapy (HDCT) in patients with high-risk medulloblastoma (MB). METHODS: Newly diagnosed high-risk MB patients (metastatic disease, postoperative residual tumor >1.5 cm2 , or large cell/anaplastic histology) over 3 years of age were enrolled in this study. Two cycles of pre-RT chemotherapy, radiotherapy (RT) including reduced-dose CSRT (23.4 or 30.6 Gy), four cycles of post-RT chemotherapy, and tandem HDCT were administered. NanoString and DNA sequencing were performed using archival tissues. RESULTS: In all, 40 patients were enrolled, and molecular subgrouping was possible in 21 patients (2 wingless, 3 sonic hedgehog, 8 Group 3, and 8 group 4). All patients including two patients who experienced progression during the induction chemotherapy underwent HDCT. Relapse/progression occurred only in four patients (5-year cumulative incidence [CI] 10.4 ± 0.3%). However, six patients died from treatment-related mortality (TRM) (four acute TRMs and two late TRMs) resulting in 18.5 ± 0.5% of 5-year CI. Taken together, the 5-year event-free survival and overall survival were 71.1 ± 8.0% and 73.2 ± 7.9%, respectively. Late effects were evaluated in 25 patients and high-tone hearing loss, endocrine dysfunction, dyslipidemia, and growth retardation were common. CONCLUSIONS: The strategy using tandem HDCT following reduced-dose CSRT showed promising results in terms of low relapse/progression rate; however, the high TRM rate indicates that modification of HDCT regimen and careful selection of patients who can benefit from HDCT will be needed in the future study.

High-dose intravenous methotrexate in the management of breast cancer with leptomeningeal disease: Case series and review of the literature.

Leptomeningeal metastasis (LM) in breast cancer is associated with significant morbidity and mortality. While there is currently no standard therapy, treatment options include craniospinal radiotherapy, intrathecal chemotherapy and systemic chemotherapy. Craniospinal radiotherapy has not demonstrated improved survival and intrathecal chemotherapy is often poorly tolerated due to associated neurotoxicity. The use of systemic chemotherapy can be limited by inadequate central nervous system penetration. High-dose systemic methotrexate administered intravenously (HD-MTX), has been reported to improve quality of life and provide durable remissions for LM in breast cancer. We present three cases of metastatic breast cancer and LM with prolonged survival after administration of HD-MTX. Based on our observations and review of the literature, HD-MTX seems to be a viable treatment option for patients with LM in breast cancer, and in select cases, the use of HD-MTX, as part of a multimodality treatment plan, may be associated with prolonged survival.

SIOPE - Brain tumor group consensus guideline on craniospinal target volume delineation for high-precision radiotherapy.

OBJECTIVE: To develop a consensus guideline for craniospinal target volume (TV) delineation in children and young adults participating in SIOPE studies in the era of high-precision radiotherapy. METHODS AND MATERIALS: During four consensus meetings (Cambridge, Essen, Liverpool, and Marseille), conventional field-based TV has been translated into image-guided high-precision craniospinal TV by a group of expert paediatric radiation oncologists and enhanced by MRI images of liquor distribution. RESULTS: The CTVcranial should include the whole brain, cribriform plate, most inferior part of the temporal lobes, and the pituitary fossa. If the full length of both optic nerves is not included, the dose received by different volumes of optic nerve should be recorded to correlate with future patterns of relapse (no consensus). The CTVcranial should be modified to include the dural cuffs of cranial nerves as they pass through the skull base foramina. Attempts to spare the cochlea by excluding CSF within the internal auditory canal should be avoided. The CTVspinal should include the entire subarachnoid space, including nerve roots laterally. The lower limit of the spinal CTV is at the lower limit of the thecal sac, best visible on MRI scan. There is no need to include sacral root canals in the spinal CTV. CONCLUSION: This consensus guideline has the potential to improve consistency of craniospinal TV delineation in an era of high-precision radiotherapy. This proposal will be incorporated in the RTQA guidelines of future SIOPE-BTG trials using CSI.

Highly Conformal Craniospinal Radiotherapy Techniques Can Underdose the Cranial Clinical Target Volume if Leptomeningeal Extension through Skull Base Exit Foramina is not Contoured.

AIMS: Craniospinal irradiation (CSI) remains a crucial treatment for patients with medulloblastoma. There is uncertainty about how to manage meningeal surfaces and cerebrospinal fluid (CSF) that follows cranial nerves exiting skull base foramina. The purpose of this study was to assess plan quality and dose coverage of posterior cranial fossa foramina with both photon and proton therapy. MATERIALS AND METHODS: We analysed the radiotherapy plans of seven patients treated with CSI for medulloblastoma and primitive neuro-ectodermal tumours and three with ependymoma (total n = 10). Four had been treated with a field-based technique and six with TomoTherapy™. The internal acoustic meatus (IAM), jugular foramen (JF) and hypoglossal canal (HC) were contoured and added to the original treatment clinical target volume (Plan_CTV) to create a Test_CTV. This was grown to a test planning target volume (Test_PTV) for comparison with a Plan_PTV. Using Plan_CTV and Plan_PTV, proton plans were generated for all 10 cases. The following dosimetry data were recorded: conformity (dice similarity coefficient) and homogeneity index (D2 - D98/D50) as well as median and maximum dose (D2%) to Plan_PTV, V95% and minimum dose (D99.9%) to Plan_CTV and Test_CTV and Plan_PTV and Test_PTV, V95% and minimum dose (D98%) to foramina PTVs. RESULTS: Proton and TomoTherapy™ plans were more conformal (0.87, 0.86) and homogeneous (0.07, 0.04) than field-photon plans (0.79, 0.17). However, field-photon plans covered the IAM, JF and HC PTVs better than proton plans (P = 0.002, 0.004, 0.003, respectively). TomoTherapy™ plans covered the IAM and JF better than proton plans (P = 0.000, 0.002, respectively) but the result for the HC was not significant. Adding foramen CTVs/PTVs made no difference for field plans. The mean Dmin dropped 3.4% from Plan_PTV to Test_PTV for TomoTherapy™ (not significant) and 14.8% for protons (P = 0.001). CONCLUSIONS: Highly conformal CSI techniques may underdose meninges and CSF in the dural reflections of posterior fossa cranial nerves unless these structures are specifically included in the CTV.

[Application of Whole Body Localization Technique in the Craniospinal Intensity-modulated Radiotherapy].

The craniospinal radiotherapy method was studied by using the whole body positioning frame and base dose plan compensation (BDPC) technique.11 patients with central nervous system malignancies in our hospital were studied. Use whole body positioning frame with the head-neck shoulder and body membrane to immobilize posture, then use BDPC for the intensity-modulated radiotherapy. Target area conformability index(CI), homogeneity index (HI), dose of endangerment organ (OAR) and beam connecting dose distribution are evaluated. The use of base-dosecompensation intensity-modulated plan combined with whole-body positioning technology improves the target area conformability and target uniformity, simplifies the design of craniospinal radiotherapy, improves the placement accuracy and ensure good placement repeatability. We measure beam connecting dose distribution. Cold and hot spots do not appear, and calculated values are basically identical. The application of whole-body positioning technique combined with BDPC optimization method in the treatment of the craniospinal radiotherapy meets the clinical requirements of dosimetry. Moreover, it is simple and can improve the treatment planning efficiency.

Intrathecal Methotrexate and Craniospinal Radiotherapy Can Be an Effective Treatment of Carcinomatous Meningitis in Patients with Breast Cancer: Case Reports.

INTRODUCTION: Carcinomatous meningitis in breast cancer occurs as a complication in up to 5% of all cases. It is a very devastating diagnosis, with a median patient survival of about 3 months. Treatment is very controversial, and different modalities of treatment have been used but none of them show significant benefit for overall survival. CASE REPORTS: We report 2 cases of carcinomatous meningitis in breast cancer patients. They received a similar treatment of a combination of intrathecal (IT) methotrexate followed by craniospinal radiotherapy. Both patients survived for many years after treatment and are in complete clinical and radiological remission. CONCLUSION: Meningeal metastasis from breast cancer can be very effectively treated with IT and/or systemic chemotherapy followed by craniospinal radiotherapy. Further studies are needed to determine the effectiveness of this sequential combination of chemotherapy with radiotherapy.

Clinical outcome and efficacy of current anti-leukemic therapy for leptomeningeal involvement in acute myeloid leukemia.

We investigated risk factors and outcome in acute myeloid leukemia (AML) patients with leptomeningeal involvement. Medical records of patients with non-promyelocytic AML at Seoul National University Hospital from January of 2000 to November of 2013 were reviewed. Leptomeningeal involvement was defined as the presence of atypical or malignant hematopoietic cells in the cerebrospinal fluid. Among 775 patients with AML, 141 patients (18.2 %) underwent cerebrospinal fluid examination. Leptomeningeal involvement of AML, confirmed in 38 patients (4.9 %), was associated with high white blood cell count and high level of lactic. There were seven patients in the favorable risk group (19.4 %), 21 in the intermediate risk group (58.3 %), and eight in the adverse risk group (22.2 %). Twenty-eight patients (85.7 %) developed leptomeningeal involvement during relapse status or refractory status. Thirty-one patients (81.6 %) received intrathecal chemotherapy, and whole-brain and/or craniospinal radiotherapy was conducted in 10 patients (27.0 %). The rate of complete remission after induction chemotherapy was 63.2 %. Median overall survival was 9.9 months. Radiotherapy and complete remission after the first induction chemotherapy were associated with longer overall survival. Leptomeningeal involvement in acute myeloid leukemia is rare, but relatively common in relapsed status or refractory status. Craniospinal radiotherapy and complete remission after induction chemotherapy were found to favorable prognostic factors.